Abstract

Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAC) results in a pCR in 30-35% of TNBC patients (pts), which is associated with improved recurrence-free and overall survival (RFS/OS). Thus, pCR rates may be useful in evaluating novel regimens in TNBC. In advanced TNBC, platinum analogues like Cb are active and addition of B to chemotherapy increases response rates and time to progression. CALGB 40603 is a 2×2 randomized phase II study designed to determine if the addition of either Cb or B to standard NAC significantly increases pCR rates in TNBC.

Methods: Pts had operable clinical stage II-III TNBC, defined as hormone receptors <10% and HER2 IHC 0-1+ or FISH <2.0 in IHC 2+. Pretreatment biopsies for correlative studies were required. Using a factorial design, pts received P 80 mg/m2 weekly x 12 followed by doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 q2wks x 4 (ddAC) with or without Cb AUC 6 q3wks x 4 during P and with or without B 10 mg/kg q2wks x 9. Surgery was performed 4-8 wks later. Post-op therapy was not specified. The primary endpoint is pCR (breast), defined as the absence of residual invasive disease (ypT0/is). Secondary endpoints include pCR (breast/axilla) (ypT0/isN0), toxicities, adverse events (AEs), RFS and OS. The primary analysis is factorial for main effects of Cb and B and their interaction; statistical power assumed no interaction. Analysis is by intent-to-treat; pts not taken to surgery are considered non-pCRs.

Results: 454 pts enrolled, median age 48, stage II 68%/stage III 32%. Of 354 pts with treatment data, 59 did not complete NAC, 30 withdrew due to AEs, more often with B vs. not (11.5% vs. 3.5%). B was discontinued in 23% of assigned pts vs. 6-13% for other agents. Grade 3-4 neutropenia (56% vs. 20%) and thrombocytopenia (22% vs. 4%) were more common with Cb vs. not, while grade 3 hypertension was more common with B vs. not (11% vs. <1%). Febrile neutropenia, usually during ddAC, was more common in pts who received both Cb and B (19% vs. others 7%). Unaudited pCR results for the first 369 pts, with effects reported as increments in pCR (95% CI), assuming no interaction, are as follows:

There is no evidence of an interaction between the effects of Cb and B (p = 0.64 and 0.44, for breast and breast/axilla, respectively).

Conclusions: Preliminary results suggest that adding Cb or B to standard NAC significantly increases pCR rates in stage II-III TNBC. These increases are additive, with pCR (breast) in 60.6% and pCR (breast/axilla) in 50% of pts who received both. Complete and confirmed results will be reported, including pCR rates for basal-like tumors vs. not. Pts will be followed for RFS/OS to assess the impact of pCR on these endpoints. Conduct of the trial was supported by grants from the NIH (ACTNOW and CA31946/CA33601), Genentech and the BCRF. Clinical trial information: NCT00861705.